Studies of the binding properties of opioid drugs and peptides at specific sites in the brain and other organs have suggested the existence of several types of opioid receptors. In the central nervous system (CNS), good evidence has been demonstrated for at least three categories of opioid receptors: .mu. (mu), .kappa. (kappa) and .delta. (delta). The established opioid antagonists naloxone and naltrexone bind to all three types of receptors, with greatest affinity for the mu receptor.
The mu receptor is thought to mediate several components of opioid drug effects including supraspinal analgesia, respiratory depression, euphoria, and physical dependence. Because of their strong mu antagonist activity, naloxone type antagonists are used for the treatment of opioid overdose toxicity (especially respiratory depression), the diagnosis of opioid dependence, and for the treatment of opioid addiction.
Naloxone type antagonists also have demonstrated effects in testing symptoms not specifically related to mu agonist activity. Naloxone has been shown to improve hemodynamic parameters in a variety of animal models of hemorrhagic, septic, and neurogenic shock. In these models, however, effective doses of naloxone are several orders of magnitude higher than doses useful in reversing mu mediated effects, suggesting that the opioid antagonist effectiveness of naloxone is being mediated through other opioid receptor systems (kappa, delta, etc.). Additionally, naloxone type antagonists often have limited effectiveness in these systems. Dose-response curves may plateau at less than 100% effectiveness or even show loss of effectiveness at higher doses (inverted U-shaped dose response curves), possible indicators of partial or counteracting activities. The involvement of kappa mediation in these systems has been suggested in several studies. In spinal trauma or ischemia, the prototypical kappa agonist opioid peptide dynorphin has been implicated as a major factor in the development of neurologic pathophysiology (Holaday, J. W., Faden, A. I., "Naloxone Acts at Central Opiate Receptors to Reverse Hypotension, Hypothermia, and Hypoventilation in Spinal Shock", Brain Research, 189, 295-299, 1980). In animal studies of spinal cord injury using a "spinal stroke" model in the rabbit, naloxone was less effective than WIN 44,441-3 (an opioid antagonist with enhanced activity at the kappa receptor), suggesting that kappa antagonist properties may be of greater importance than mu antagonist activity in the therapeutic effectiveness of antagonists in these systems (Faden, A. I., Jacobs, T. P., "Opiate Antagonist WIN 44,441-3 Stereospecifically Improves Neurologic Recovery After Ischemic Spinal Injury", Neurology, 35, 1311-1315, 1985).
Another serious problem for which help is often sought is obesity. It can lead to a number of serious side-effects, not the least of which is an increased risk of cardiovascular disease. A number of appetite suppressants are currently available for the treatment of obesity, but none is completely satisfactory.
Several animal studies have suggested a role of the opioid system in the control of food intake. Kappa agonist agents such as ethylketocyclazocine and U-50,488H have been shown to be more potent stimulators of feeding than the mu agonist morphine (Morley, J. E., Levine, A. S., Grace M., Kneip, J., "An Investigation into the Role of Kappa Opiate Receptor Agonists in the Initiation of Feeding", Life Sci., 31, 2617, 1982.) Autoradiographic studies have shown that high densities of kappa receptors are found localized within specific brain areas known to regulate ingestive behaviors (Lynch, W. C., Watt, J., Krall, S., Paden, C. M., "Autoradiographic Localization of Kappa Opiate Receptors in CNS Taste and Feeding Areas", Pharmacology, Biochemistry & Behavior, 22, 699-705, 1985). Naloxone and naltrexone have been shown to decrease food intake in several animal species, but here again the effective doses are much larger than those useful in reversing mu mediated effects. Thus, a more selective kappa antagonist could possibly have a greater degree of therapeutic effectiveness than naloxone and naltrexone in decreasing food intake behavior.
Kappa selective opioid antagonists have demonstrated some improved utility in treatment of shock, stroke, and the control of food intake. Other suggested therapeutic utilities for the kappa selective antagonists include modulation of endocrine dysfunctions since kappa receptors have shown effects in mediating endocrine function.
Thus, it would be highly desirable to obtain a compound which has a significant degree of selectivity for the kappa receptor, allowing antagonist effects to be achieved at doses not complicated by mu antagonist effects or by effects not mediated through opioid receptors. A selective kappa antagonist may provide an agent which is more fully effective than a non-selective antagonist in those conditions (shock, stroke, obesity, endocrine dysfunction) whose etiology appears related to kappa function.
E. Ciganek, U.S. Pat. No. 4,477,456, describes compounds of the classes, 1,2,3,4,5,6,7,7a-octahydro-4a,7-ethanobenzofuro[3,2-e]isoquinolines and 1,2,3,4,5,6,7,7a-octahydro-4a,7-ethenobenzofuro[3,2-e]isoquinolines that exhibit analgesic, narcotic antagonist, mixed analgesic/narcotic antagonist, and/or anorexigenic properties. These compounds have Formula (I): ##STR1## wherein: R.sup.1 is H, C.sub.1 -C.sub.10 alkyl, CH.sub.2 --R.sup.6, C.sub.2 H.sub.4 (C.sub.6 H.sub.4)R.sup.7, or (CH.sub.2).sub.n CN, in which n=1-3;
R.sup.2 is H, OH, C.sub.1 -C.sub.2 alkoxy, or C.sub.2 -C.sub.12 acyloxy of an alkanoic acid; PA1 R.sup.3 is H, C.sub.1 -C.sub.8 alkyl, or C(OH)(R.sup.5); PA1 a is a single bond or a double bond; PA1 R.sup.4 is H or C.sub.1 -C.sub.8 alkyl; PA1 R.sup.5 is H, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.3 -C.sub.8 cycloalkyl, or (CH.sub.2).sub.m --C.sub.6 H.sub.5 in which m=0-4; PA1 R.sup.6 is CH.dbd.C(R.sup.8)(R.sup.9), C.tbd.CH, C.sub.3 -C.sub.6 cycloalkyl, phenyl, 2-thienyl, 2-furyl, 2-tetrahydrofuryl, methyl substituted 2-tetrahydrofuryl; PA1 R.sup.7 is H, C.sub.1 -C.sub.3 alkyl, OCH.sub.3, Cl, Br, or F; and PA1 R.sup.8 and R.sup.9 are independently H, CH.sub.3, or Cl. PA1 R.sup.1 is n-propyl or CH.sub.2 R.sup.5 ; PA1 R.sup.2 is H, alkyl of 1-2 carbons, C.sub.2-12 acyl of an alkanoic acid, or ##STR3## R.sup.3 is H or alkyl of 1-8 carbons; R.sup.4 is H, alkyl of 1-8 carbons; alkenyl of 1-8 carbons, cycloalkyl of 3-8 carbons, or (CH.sub.2).sub.m C.sub.6 H.sub.5 in which m is 0-4 inclusive; PA1 R.sup.5 is CH.dbd.C(R.sup.6)(R.sup.7), C.tbd.CH, or cyclopropyl provided that when R.sup.5 is cyclopropyl, then R.sup.2, R.sup.3 and R.sup.4 are independently H and R.sup.8 is CH.sub.3 or (CH.sub.2).sub.n C.sub.6 H.sub.5 in which n is 3-4 inclusive; PA1 R.sup.6 and R.sup.7 independently are H, CH.sub.3 or Cl; PA1 R.sup.8 is alkyl of 1-8 carbons, alkenyl of 1-8 carbons, cycloalkyl of 3-8 carbons, or (CH.sub.2).sub.n C.sub.6 H.sub.5 in which n is 3-4 inclusive; PA1 X is O or S; PA1 Y and Z independently are H, OR.sup.9, NHR.sup.9, or NR.sup.9 R.sup.10, provided at least one of Y or Z is OR.sup.9, NHR.sup.9, or NR.sup.9 R.sup.10 ; PA1 R.sup.9 is H, alkyl of 1-4 carbons, or COR.sup.11 ; PA1 R.sup.10 is alkyl of 1-4 carbons, or COR.sup.11 ; and PA1 R.sup.11 is H or alkyl of 1-4 carbons. PA1 (a) R.sup.1 is n-propyl or cyclopropylmethyl, provided that when R.sup.1 is cyclopropylmethyl, then R.sup.2, R.sup.3 and R.sup.4 are H, and R.sup.8 is CH.sub.3 or (CH.sub.2).sub.n C.sub.6 H.sub.5 in which n is 3-4; or PA1 (b) R.sup.2 is H; or PA1 (c) R.sup.3 and R.sup.4 are H; or PA1 (d) R.sup.8 is alkyl of 1-3 carbons; or PA1 (e) X is O; or PA1 (f) a is a single bond. PA1 (a) R.sup.1 is n-propyl or cyclopropylmethyl; PA1 (b) R.sup.2, R.sup.3 and R.sup.4 are H; PA1 (c) R.sup.8 is alkyl of 1-3 carbons; and PA1 (d) a is a single bond. PA1 (a) 5-Methoxymethyl-3-n-propyl-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethanobenzofuro [3,2-e]isoquinolin-9-ol; and PA1 (b) 3-Cyclopropylmethyl-5-methoxymethyl-1,2,3,4,5,6,7,7a-octahydro-4a,7-ethano benzofuro[3,2-e]-isoquinolin-9-ol.
A coassigned, pending application U.S. Ser. No. 774,025, filed Sept. 9, 1985, discloses a process for preparing compounds of Formula (I) and intermediates thereof.